The results of retransplantation have consistently been worse than those of primary transplantation, although they have been improving (1–4). There has been a vigorous debate regarding the allocation of grafts for retransplantation because up to 29% of children in some series have eventually needed to undergo retransplantation (1,5). However, retrans- plantation rates have been gradually decreasing over recent years (2,6). Pediatric retransplantation also contributes significantly toward late morbidity in this high-risk population (7). There have been relatively few reports on short-term and long-term outcomes of retransplantation in children (1). The aim of this study was to assess the short-term and long-term outcome, morbidity, and mortality after retransplantation in children. Further, the influence of the time of retransplantation and the impact of widening expertise in retransplantation have also been assessed.
PATIENTS AND METHODS
During an 11-year period from January 1990 to March 2001, 50 children underwent retransplantation at King’s College Hospital. Of these, 9 received a second retransplant and 1 received a third retransplant, for a total of 60 retransplantations. A total of 450 pediatric transplantations were performed during this period, for a retransplantation rate of 13.3%. Of the 50 patients who underwent retransplantation, 28 (56%) were boys and 22 were girls, with a median age at retransplantation of 4 years (range, 54 days to 16 years) and a median weight of 15 (range, 3 to 80) kg. Forty-one children initially underwent transplantation for chronic liver disease; of these, 25 (50% of the entire cohort) had previously undergone a Kasai portoenterostomy for extrahepatic biliary atresia. The interval between the initial transplantation and the retransplantation was a median of 61 (range, 1 to 1510) days. Twenty-three (46%) patients underwent retransplantation within a month of their initial transplantation (median, 10 days) and were classified as “early retransplants.” Twenty-seven received a retransplantation more than 1 month after the initial transplantation (median, 177 days) and were classified as “late retransplants.”
The indications for retransplantation are listed in Table 1 and include hepatic artery thrombosis (HAT) in 18 (36%) and chronic rejection in 13 (26%) patients. The most common reasons for retransplantation in the early retransplantation group were vascular complications (predominantly HAT) and graft dysfunction. The most common reasons for late retransplantation in 27 patients were chronic rejection and late vascular and biliary complications. Nineteen (38%) patients were in the intensive care unit (ICU) at the time of retransplantation, 23 (46%) were inpatients on a specialized pediatric hepatology ward, and 8 (16%) were admitted from home. Nearly a quarter of all patients (24%) were ventilated.
The median donor age was 18 (range, 2–59) years, with a median weight of 60 (range, 14–95) kg. The median donor ICU stay was 2.5 days, and more than two thirds (68%) of donors were on inotropic support. Ten (20%) patients underwent retransplantation with a whole liver, whereas the remainder underwent segmental liver transplantation with a reduced liver in 30 (60%), a split liver (SpLT) in 9 (18%; one of which was used as an auxiliary graft), and a living-related graft in 1 (2%). Of the 40 segmental retransplantations, the left lateral segment (LLS) was used in 18 (45%), the left lobe in 17 (42.5%), and a reduced right lobe in 2 (5%); 3 (7.5%) children, younger than 10 months and weighing less than 7 kg, had reduced LLS grafts (monosegments). Veno-venous bypass was not used, and all but one child had Roux-en-Y hepaticojejunostomy for biliary reconstruction.
The entire cohort was further divided into two chronologic groups: Phase I retransplantations performed between 1990 and 1995 (n=22); and phase II retransplantations performed after 1995 (n=28). The use of a whole liver for retransplantation decreased in phase II transplantations (3 of 28 in phase II; 7 of 22 in phase I), with an increasing use of split livers for retransplantation (8 of 28 in phase II; 1 of 22 in phase I). This was associated with a lower median age and weight of children undergoing retransplantations in the second phase (median age 7.5 years and weight 23 kg in phase I and 2.6 years and 11 kg, respectively, in phase II). All patients who underwent retransplantation received immunosuppression initially with cyclosporine-based or tacrolimus-based regimens. The median post-retransplantation follow-up was 73 (range, 6–139) months. One-year, 3-year, and 5-year survival curves were calculated for the entire cohort and subgroups using the Kaplan-Meier method. Survival differences between subgroups were compared using a log-rank analysis. Cox regression analysis was performed to identify factors influencing the outcome after retransplantation.
The overall retransplantation rate for our pediatric liver transplantation program was 13.3%. In phase I, 140 pediatric transplantations were performed, 22 (15.7%) of which were first retransplantations. Of the 310 pediatric transplantations performed in phase II, 28 (9%) were first retransplantations (P =0.05, compared with phase I).
Of 50 patients, 6 developed graft dysfunction in the immediate postoperative period; 4 (8%) patients developed early graft dysfunction (EGD), and 2 (4%) experienced primary nonfunction (PNF). Of these, four patients were ventilated in the ICU preoperatively and two were ward based. All died within 1 month of undergoing retransplantation. The causes of death with EGD were coagulopathy, recurrent bleeding, and sepsis in two patients and sepsis and multiorgan failure in two patients, one of whom also had venous outflow obstruction in an LLS split liver graft. Both patients with PNF died on the second postoperative day with multiorgan failure and coagulopathy and were deemed too unstable to be considered for retransplantation. Five of these six patients (four with EGD and one with PNF) belonged to both the early retransplants and phase I groups. Of these, four had undergone retransplantation for vascular complications, which were HAT in three patients and venous outflow obstruction in one patient. The other PNF occurred early in phase II. There was no case of graft dysfunction in the last 21 pediatric retransplantations.
Two (4%) patients developed HAT after retransplantation. One child, who received a reduced LLS graft, was diagnosed on ultrasonography on day 3 and underwent surgical revision of the anastomosis without success. A second child, with a whole liver retransplant, developed HAT at 6 months in association with left lobe necrosis and sepsis. Both patients underwent transplantation for the third time. Four (8%) children, all of whom were LLS recipients, developed venous outflow obstruction at varying intervals after retransplantation. One child, who received a SpLT regraft, developed hepatic venous outflow obstruction associated with EGD and died on the 17th postoperative day. Three children with reduced grafts developed late incomplete vena caval occlusion at 7 months, 1 year, and 8 years, respectively. The first child underwent balloon dilatation of the caval stenosis 7 months after retransplantation. Unfortunately, he had recurrence of caval stenosis and underwent retransplantation again. The second child had partial caval obstruction associated with graft hypertrophy 1 year after retransplantation, which was dilated by a transjugular approach; and the third child, who had undergone retransplantation for outflow obstruction because of acute Budd-Chiari syndrome, developed recurrent thrombosis 8 years after retransplantation and was managed by a caval stent.
There have been no portal venous complications. Arterial complications occurred in the late retransplant group, whereas hepatic venous and caval complications occurred in the early retransplant group. Three of these six vascular complications occurred in the phase I group (two HAT and one venous outflow obstruction) and three in the phase II group.
Five (10%) patients developed biliary complications, three in phase I and two in phase II transplantations, all of whom had had a Roux-en-Y biliary reconstruction at retransplantation. Two patients developed minor biliary leaks, one of whom had a percutaneous aspiration and the other, a laparotomy and washout; the first patient had received a whole liver and the second, an LLS living-related liver transplantation. One patient developed an anastomotic stricture. This patient, who initially received a transplant for biliary atresia, underwent retransplantation with a reduced graft for recurrent biliary sepsis. He then developed an anastomotic stricture and underwent revision of his hepaticojejunostomy. Another patient developed a nonanastomotic stricture of the extrahepatic biliary tree and underwent endoscopic dilatation 13 months after retransplantation. The fifth patient developed rising liver enzymes associated with an intrahepatic stricture in his reduced LLS graft, 8 months after retransplantation, and had repeat percutaneous transhepatic dilatations. Both leaks and the extrahepatic stricture occurred in patients undergoing late retransplantation. All patients had normal liver function at their last follow-up.
Four (8%) patients underwent laparotomy in the immediate postoperative period for intra-abdominal bleeding. Three had received reduced liver transplantations and one, a whole liver graft; no SpLTs had postoperative bleeding. The site of bleeding was extrahepatic in two patients, from a liver biopsy in 1 patient, and associated with coagulopathy in the fourth patient. Of these four patients, three underwent retransplantation before 1993. Four patients underwent laparotomy for other intra-abdominal problems including subhepatic collection, intra-abdominal abscess, colonic perforation, and Roux loop adhesive obstruction; a further two patients underwent laparotomy for suspected peritonitis. Four (8%) patients developed posttransplant lymphoproliferative disorder at a median of 9 (range, 4–48) months after retransplantation, and three died at 5, 11, and 18 months, respectively, after retransplantation.
Of 50 patients who received retransplants, 9 (18%) underwent transplantations for a third time: for HAT in 2 patients (5 days and 15 months after retransplantation, respectively) and chronic rejection in 5 patients (3, 4, 4, 7, and 14 months, respectively). One patient, who underwent retransplantation with an ABO-mismatched graft for recurrence of non-A non-B hepatitis, experienced acute graft rejection and underwent transplantation for the third time, 2 weeks after her second transplantation. The ninth patient developed late progressive suprahepatic venacaval occlusion and required retransplantation again, 2 years after the first retransplantation. The Kaplan-Meier survival of these nine patients after the second retransplantation, during a median follow-up period of 73 months, was 53.3% at 1 year and 40% at 3 years.
All patients were followed up for at least 6 months. The Kaplan-Meier patient survival rates for the entire cohort (n=50) from the time of retransplantation were 71.7% at 1 year and 64.7% at 3 and 5 years. The corresponding graft survival rates were 65.6% at 1 year and 56.7% at 3 and 5 years (Fig. 1). These figures are significantly lower than those for children undergoing primary transplantation at our center, with 1-year, 3-year, and 5-year patient survival rates of 88%, 84%, and 82.3%, respectively (P =0.003), during a median follow-up period of 56 months. There were 17 deaths in the retransplant cohort during the follow-up period, 9 of which occurred in the first month. The majority of children who died within 1 month had poor graft function or sepsis and multiorgan failure; of these, two received a third transplant during the same admission. The majority of late deaths were a result of chronic rejection and associated complications.
There were seven deaths in the early retransplantation group (n=23), all within 1 year and 6 occurred in the postoperative period before discharge (median follow-up, 79 months; range, 8-129 months). The Kaplan-Meier patient survival rates were 69.6% at 1, 3, and 5 years, respectively (Fig. 2). In the late retransplantation group (n=27), there were 10 deaths, 3 of them in the early postoperative predischarge period (median follow-up, 69 months; range, 6–139 months). The Kaplan-Meier patient survival rates in this group were 73.4% at 1 year and 60.7% at both 3 and 5 years (P =0.8, not significant, compared with the early retransplant group). The graft survival rates in the early retransplant group were 69.6% at 1 year and 64.6% at 3 and 5 years, whereas that in the late retransplant group, rates were 62.2% at 1 year and 49.4% at 3 and 5 years (P =0.5, not significant).
Comparing the survival rates between the two phases between 1990 to 1995 and 1995 to 2001, there were nine deaths in phase I and eight in phase II. Significantly, more deaths occurred in the immediate postoperative period in the phase I group compared with phase II (seven in phase I, two in phase II;P <0.05, significant). The Kaplan-Meier survival rates of patients in the phase I group were 68.2% at 1 year and 59.1% at both 3 and 5 years (Fig. 3), whereas rates for the phase II group were 74.2% at 1 year and 70.1% at both 3 and 5 years (P =0.4, not significant). The corresponding graft survival rates were 59.1% at 1 year and 50% at both 3 and 5 years in the phase I group and 70.4% at 1 year and 61.6% at both 3 and 5 years in the phase II group (P =0.3, not significant).
The overall survival of patients with late retransplants was still significantly inferior (P =0.01) compared with that after primary transplantation; however, survival of patients in phase II retransplants was not statistically different (P =0.09) from that observed after primary transplantation at our center.
Perioperative variables were analyzed using Cox regression to identify factors significantly influencing survival after retransplantation (Table 2). Patients who underwent first transplantation for chronic liver disease had a significantly better outcome after retransplantation compared with those who initially underwent transplantation for acute liver failure (P <0.01). Higher preoperative serum creatinine level before retransplantation was associated with a poorer outcome (P <0.01) as was higher serum bilirubin level (P =0.02). Finally, patients who initially underwent transplantation for biliary atresia had a better survival after retransplantation than those who underwent transplantation for other indications, although the survival difference was not statistically significant (P =0.08). There was no difference in survival between patients receiving a whole or segmental regraft. Other factors such as patient age and weight at retransplantation, donor and recipient sex mismatch, United Network for Organ Sharing status, graft cold and warm ischemic times, and donor factors did not seem to significantly influence the outcome.
Graft failure remains a significant problem in children undergoing liver transplantation. Despite advances in surgical techniques, immunosuppression, and organ preservation, it can occur in up to 30% of children within the first year (8). Our overall pediatric retransplantation rate of 13.3% during an 11-year period is comparable with that reported by others for adults and children (2,6,9–11) and has significantly decreased from 15.7% in phase I to 9% in phase II.
Retransplantation is also a major cause of long-term morbidity and complications in children who survive the procedure (7). There is little written in the literature about immediate graft function and postoperative complications after pediatric liver retransplantation. Eight percent of our retransplant recipients experienced EGD and 4% experienced PNF; survival of these patients is poor. Children undergoing emergency or early retransplantation seem to be more prone to develop graft dysfunction. In addition, these patients are hemodynamically unstable with multiorgan failure and may not perfuse the new graft satisfactorily, which may contribute to the higher incidence of graft dysfunction observed. Graft dysfunction may also be related to the level of surgical experience and immunosuppression, because the majority of these cases occurred in the early phase of the program, before improvements in these two areas.
The incidence of HAT after pediatric retransplantation has been reported to be up to 10% (1,5). HAT was identified in two (4%) of our patients at 3 days and 6 months after retransplantation, respectively; both underwent further retransplantation. The child with late HAT occurring in two successive transplants was identified as being anticardiolipin antibody positive. This case emphasizes that underlying prothrombotic disorders need to be screened for in children with unexplained HAT before considering further intervention or retransplantation. It is unclear whether collateral circulation develops as readily in patients who undergo retransplantation. In our experience, reduced or split grafts seem to develop a collateral arterial supply more readily than whole grafts.
Sieders (1) has reported a 15% incidence of outflow obstruction after pediatric retransplantation; four (8%) children experienced this complication in our series. The patient with hepatic venous outflow obstruction and EGD was the first LLS SpLT we performed. Of note, three patients who received LLS reduced liver retransplants developed late partial caval obstruction at varying intervals after their retransplantation. All of these children had had a standard liver implantation with caval replacement at their initial transplantation and, subsequently, a piggyback implantation of an LLS at retransplantation, retaining the original suprahepatic caval anastomosis, resulting in two separate outflow anastomoses close to each other. Their presenting symptoms, namely lower limb edema, ascites, and hepatomegaly, were those of inferior venacaval obstruction. None of these patients had significant graft dysfunction. All patients have undergone percutaneous transvenous stenting and dilatation, two via the internal jugular vein and one via the femoral vein. Optimal caval blood flow has been demonstrated in two, whereas the third child underwent retransplantation because of progressive venous occlusion. Technically, the “triangulation” technique (12), which involves vertically enlarging the left hepatic venous orifice on the recipient cava inferiorly, is helpful in reducing the incidence of outflow obstruction, while implanting a split or a reduced LLS on the recipient left hepatic vein orifice. There were no cases of portal vein thrombosis.
Five (10%) patients developed biliary complications after retransplantation, which compares with a 9% incidence reported by Sieders (1). Both the leaks resolved with intervention, and none of the five patients have developed long-term complications. Significantly, no biliary complications occurred in the nine SpLTs, which are considered to be more prone to biliary complications (13). Of note, there have been no biliary complications in the 20 retransplantations performed over the last 4 years, although only 3 of these were whole liver grafts. Our incidence of postoperative bleeding (8%) compares with a 12% incidence reported by Sieders (1).
Nine children underwent a third transplantation, five for chronic rejection. Notably, three (60%) of these five had undergone retransplantation initially for chronic rejection. Seven patients belonged to the late retransplants group. Offering a third graft to children in this era of increasing organ shortage may be considered contentious because survival after a third transplantation is poor in both children and adults, although the numbers in such series are small (5,10,14,15). It is important to discuss with the family the outcome of retransplantation in children with chronic rejection, because they are more likely to repeatedly reject their subsequent grafts. In an earlier series reported from our institution (16), over a half (56%) of all first retransplantations were performed for chronic rejection, whereas in the current series, the proportion is down to 26%. Thus it would seem that the overall incidence of irreversible chronic rejection is on the decline. This could, in part, be a result of the introduction of tacrolimus and mycophenolate mofetil as immunosuppressive agents in clinical practice. A few patients with chronic rejection have died while awaiting retransplantation, whereas some have responded to alternative immunosuppression.
Our patient survival rates of 71.7% at 1 year and 64.7% at 3 and 5 years are comparable to those reported by others (Table 3). Patient and graft survival has consistently been found to be significantly lower in patients undergoing urgent or early retransplantation within 1 to 3 months of the initial transplantation (1,2,10,17,20,21). Most of these patients undergo retransplantation for acute insults such as PNF or HAT, and many have multisystem failure and sepsis. Patient survival in our cohort is better in the late than in the early retransplant recipients in the short-term. However, in the long-term, early retransplant recipients seem to do better. Patients undergoing early retransplantations have acute problems like PNF or HAT and are therefore more unstable and unwell at retransplantation. Consequently, the short-term mortality is significantly higher in this group, as is evident by the fact that all deaths and graft losses have occurred within 1 year of retransplantation, mostly from graft dysfunction and sepsis. Late retransplantations, however, are mostly performed for chronic rejection and although they do well in the short-term, they have a higher chance of late graft loss and death as a result of recurrence of chronic rejection. Some authors have reported survival rates in late or non-urgent retransplantations to be comparable to those with first transplantations (1,3,22). In our series, the survival in the late retransplant group is still significantly inferior to that in children at primary transplantation.
Many authors have tried to identify subgroups of patients who are likely to have a poor survival after retransplantation. Age at retransplantation, preoperative serum creatinine and serum bilirubin levels, and United Network for Organ Sharing status have been found to have an impact on patient survival (23–25). Of these, only preoperative serum creatinine and serum bilirubin levels were found to be influential factors in our series. Although some authors have found a poorer survival in retransplant recipients who originally underwent transplantation for biliary atresia (1), we have noted the reverse to be true. It is also important to note that patients who originally underwent transplantation for acute liver failure did significantly worse after retransplantation even though they were equally distributed within the early versus late and phase I versus phase II groups.
With improving graft survival after first liver transplantation, the percentage of patients needing a retransplant has been gradually falling (2,6), as confirmed in this series. Moreover, most authors report better outcome in patients who underwent retransplantation later in their program. A variety of factors, including improvements in organ preservation and immunosuppression, widening experience, and better postoperative care, have been associated with decreasing complications and increased survival rates in these patients (2,6,10,26). In our series, the biliary and vascular complications are equally distributed between the two phases; however, there has been a significant decrease in the incidence of graft dysfunction, postoperative bleeding, and in-hospital mortality in the later phase. Patient and graft survival rates in our series, too, have improved in latter years, although the difference does not reach statistical significance. More importantly, patient survival in phase II retransplantations is statistically comparable to that observed with patients who have undergone primary transplantation.
Retransplantation in children remains challenging and carries a high mortality and morbidity. Children undergoing retransplantation in emergency situations tend to have a poorer outcome, as do children who initially undergo transplantation for acute liver failure. Although overall retransplantation rates have decreased, with improving survival and better life expectancy, more children are likely to need retransplantation in the long-term. The successful use of split and living donor transplant techniques has lead to more grafts being available for the pediatric transplantation. Liver retransplantation should, therefore, be offered to children with irreversible graft failure. (18,19)
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